Disease Dementia Research Articles

Dementia Caregiving and Dialectical Tensions During the Early Days of the COVID-19 Pandemic

Caregiving for a loved one with Alzheimer's disease or related dementia presents significant challenges which were amplified throughout the COVID-19 pandemic. During this time, care partners were forced to navigate uncertain terrain as well as new and challenging relational tensions. This study investigated the experiences of dementia care partners and the relational tensions present as they managed the early days of the COVID-19 pandemic using Relational Dialectics Theory framework. By analyzing recorded support groups from the early days of the pandemic (April through June, 2020), we identified two chief tensions expressed by participants throughout their support groups: connection—independence and gratitude—frustration. Participants experienced these tensions in different ways, and they engaged in four tension management strategies ( selection, minimization, reframing, and venting and comradery) through the support group. As the pandemic progressed, participants’ tension management evolved, highlighting the complexity inherent in caring for a person with dementia during the COVID-19 pandemic.

Characterizing Physiologic Swallowing Impairment Profiles: A Large-Scale Exploratory Study of Head and Neck Cancer, Stroke, Chronic Obstructive Pulmonary Disease, Dementia, and Parkinson's Disease

Purpose: The purpose of the present study was to use a large swallowing database to explore and compare the swallow-physiology impairment profiles of five dysphagia-associated diagnoses: chronic obstructive pulmonary disease (COPD), dementia, head and neck cancer (HNC), Parkinson's disease (PD), and stroke. Method: A total of 8,190 patients across five diagnoses were extracted from a de-identified swallowing database, that is, the Modified Barium Swallow Impairment Profile Swallowing Data Registry, for the present exploratory cross-sectional analysis. To identify the impairment profiles of the five diagnoses, we fit 18 partial proportional odds models, one for each of the 17 Modified Barium Swallow Impairment Profile components and the Penetration–Aspiration Scale, with impairment score as the dependent variable and diagnoses, age, sex, and race as the independent variables with interactions between age and diagnoses and between PD and dementia (in effect creating a PD with dementia [PDwDem] group). For components with > 5% missingness, we applied inverse probability weighting to correct for bias. Results: PD and COPD did not significantly differ on 13 of the 18 outcome variables (all p s > .02). Dementia, stroke, and PDwDem all showed worse impairments than COPD or PD on five of six oral components (all p s < .007). HNC had worse impairment than all diagnoses except PDwDem for nine of 10 pharyngeal components (all p s < .006). Stroke and HNC had worse penetration/aspiration than all other diagnoses (all p s < .003). Conclusions: The present results show that there are both common and differing impairment profiles among these five diagnoses. These commonalities and differences in profiles provide a basis for the generation of hypotheses about the nature and severity of dysphagia in these populations. These results are also likely highly generalizable given the size and representativeness of the data set. Supplemental Material: https://doi.org/10.23641/asha.27478245

Are oligodendrocytes the missing link in Alzheimer's disease and related dementia research?

Are oligodendrocytes the missing link in Alzheimer's disease and related dementia research?

Changes in choroidal thickness quantified by Optical Coherence Tomography across cognitive impairment: data from the NORFACE cohort.

Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD). Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed. The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability. Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment.

The protective role of basal metabolic rate in cognitive decline: evidence from epidemiological and genetic studies.

This study aims to explore the relationship between basal metabolic rate (BMR) and cognitive impairment and assess the potential of BMR as a protective factor against cognitive decline. This investigation initially conducted a cross-sectional study of American adults from 2011 to 2014 using data from the National Health and Nutrition Examination Survey. It examined the correlation between participants' BMR and cognitive functions, exploring the association with cognitive impairment. Subsequently, publicly available genome-wide association study data was used to examine potential causal links between genetically determined BMR and specific cognitive disorders using Mendelian randomization. Cross-sectional findings revealed a significant positive correlation between higher BMR and cognitive scores. In Mendelian randomization analysis, BMR demonstrated an inverse causal relationship with Alzheimer's disease and Parkinson's dementia, suggesting BMR as a potential protective factor against these diseases. No causal links were found with vascular dementia, Lewy body dementia, and frontotemporal dementia. This study supports the role of BMR as a potential protective factor against Alzheimer's disease and Parkinson's dementia, suggesting that BMR may play an important role in preventing cognitive decline. However, due to the limitations of cross-sectional studies, further prospective studies and broader demographic samples are necessary to verify these results and explore underlying biological mechanisms. Key messages What is already known on this topic: Existing knowledge suggests a close relationship between BMR and health and cognitive functions, but detailed studies on its connection with specific cognitive impairments are still needed. What this study adds: This study found a significant positive correlation between higher BMR and cognitive improvement, potentially aiding in the prevention of Alzheimer's and Parkinson's dementia. How this study might affect research, practice, or policy: This finding guides public health strategies and personalized medicine, emphasizing the necessity for further research to validate BMR's protective effects.

Estimating the rates of dementia using administrative data linked to cohort studies.

Current estimates of dementia and Alzheimer's disease incidence and prevalence are required to understand the health needs of the elderly. We used two Australia cohort studies, administrative datasets, and data linkage techniques to estimate dementia rates in Australia. The study used Australian Longitudinal Study on Women's Health and the Health in Men Cohort Study. Records of dementia were obtained from linked sources and incidence and prevalence estimates were produced. Capture-recapture methods were used to estimate numbers of dementia cases not identified through data linkage. There were 3399 (28.5%) men with dementia identified from any source and 3767 (34.8%) women. Rates of dementia incidence and prevalence were similar between sexes but were raised in men once estimates of unidentified cases were included. Cohort studies and linked administrative data can be used together to produce current estimates of dementia prevalence and incidence comparable to other population estimates.

The prevalence and risk factors of apathy among the Canadian long-term care residents with Alzheimer's disease and related dementias.

Apathy is a prevalent and debilitating neuropsychiatric symptom among persons living with Alzheimer's disease and related dementias, particularly those residing in long-term care facilities (LTCF). Despite its profound effects on the quality of life for both residents and their caregivers, apathy remains underrecognized and poorly understood in the context of dementia care. To investigate the prevalence and biopsychosocial characteristics of apathy among newly admitted residents with dementia in Canadian LTCF using an Apathy Index derived from the interRAI Minimum Data Set (MDS) 2.0. This cross-sectional study analyzed data from newly admitted residents with dementia from various LTCF (N = 97,789) across seven Canadian provinces between 2015 and 2019. Logistic regression analysis was performed to determine the relationship between apathy and multiple variables including sociodemographic and clinical variables. The biopsychosocial model of health was used to guide analysis. The prevalence rate of apathy among the Canadian long-term care residents with Alzheimer's disease and related dementias was 13.1%. Apathy was associated with various variables including male sex, pain, use of psychotropics, high Activity of Daily Living Self-Performance Hierarchy Scale scores, depression, aggression, severe cognitive impairment, and insomnia. Preferences for certain activities such as card games, art and craft, reading, music and exercise were inversely related to apathy while gardening was not. By shedding light on this complex phenomenon within a Canadian context, we recommend that targeted interventions and improved care strategies to enhance the well-being of persons living with dementia should be prioritized in LTCF.

Mental health care needs of caregivers of people with Alzheimer's disease from online forum analysis.

Informal caregivers of people with Alzheimer's disease and related dementias (ADRD) are at risk of poor mental health. This study aimed to investigate the feasibility and validity of studying caregivers' mental stressors using online caregiving forum data (March 2018-February 2022) and natural language processing and machine learning (NLP/ML). NLP/ML topic modeling generated eight prominent topics, which we compared with qualitatively defined themes and the existing caregiving framework to assess validity. Among a total of 60,182 posts, 5848 were mental distress-related; for the ADRD patients (symptoms, medication, relocation, care duty share, diagnosis, conversation strategy) and the caregivers (caregiving burden and support). While we observed novel topics from NLP/ML-defined topics, mostly those were aligned with the existing framework. For feasibility assessment, qualitative title screening was done. The findings shed new light on the potential of NLP/ML text analysis of the online forum for informal caregivers to prepare tailored support for this vulnerable population.

Public and participant involvement as a pathway to inclusive dementia research.

The field of Alzheimer's disease and related dementias (ADRD) urgently requires inclusive research to ensure the priorities and outcomes of research apply to those most impacted. We postulate public and participant involvement (PPI) as a pathway to achieving the best science, both in research that informs health and social policy as well as in therapeutic studies to treat and prevent ADRD. This position paper aims to provide dementia researchers with evidence to understand how to apply PPI. We begin by highlighting the disparities experienced by people with dementia, including ageism, stigma of cognitive impairment, and health disparities for minoritized communities. We then provide examples of PPI in ADRD across the research lifecycle, from defining research topics of priority to those impacted by ADRD, through the design, analysis, dissemination, and translation to policy and practice. We also provide recommendations to create and maintain collaboration between researchers and communities through PPI. HIGHLIGHTS: A central premise of public and participant involvement (PPI) is collaborative relationships between researchers and community members. To build equitable partnerships, researchers must acknowledge and understand the context of research. This includes ageism, the stigma of dementia, and ongoing discrimination for many minoritized communities. Meaningful partnerships include choice, respect, shared decision making, access, inclusion, and representation. Notably, we recommend that researchers begin partnerships early in the research process and share the impact of PPI on research.

Endothelial progenitor cell-derived conditioned medium mitigates chronic cerebral ischemic injury through macrophage migration inhibitory factor-activated AKT pathway.

Chronic cerebral ischemia (CCI) is a significant health issue characterized by hypoperfusion due to damage or occlusion of the cerebral or carotid arteries. CCI may lead to progressive cognitive impairment that is considered as a prelude to neurodegenerative diseases, including dementia and Alzheimer's disease (AD). Endothelial progenitor cells (EPCs) have been implicated in vascular repair in ischemic cerebrovascular diseases, primarily by differentiating into endothelial cells (ECs) or through paracrine effects. However, the clinical transplantation of stem cell therapies remains limited. In this study, we investigated the effects of EPC-derived conditioned medium (EPC-CM) on the impaired vasculature and neurological function in a rodent model of CCI and the mechanism involved. EPC-CM was analyzed by cytokine array to identify key factors involved in angiogenesis and cellular senescence. The effects and mechanism of the candidate factors in the EPC-CM were validated in vitro using oxygen-glucose deprivation (OGD)-injured ECs and EPCs. The therapeutic effects of EPC-CM and the identified key factor were further examined in a rat model of CCI, which was induced by bilateral internal carotid artery ligation (BICAL). EPC-CM was administered via intracisternal injection one week post BICAL. The cerebral microvasculature and neurobehavior of the rats were examined three weeks after BICAL. Macrophage migration inhibitory factor (MIF) was identified as a key factor in the EPC-CM. Recombinant MIF protein promoted angiogenesis and prevented senescence in the injured EPCs and ECs. The effect was similar to that of the EPC-CM. These therapeutic effects were diminished when the EPC-CM was co-treated with MIF-specific antibody (Ab). Additionally, the vascular, motor, and cognitive improvements observed in the BICAL rats treated with EPC-CM were abolished by co-treated with MIF Ab. Furthermore, we found MIF promoted angiogenesis and anti-senescence via activating the AKT pathway. Inhibition of the AKT pathway diminished the protective effects of MIF in the in vitro study. We demonstrated that EPC-CM protected the brain from chronic ischemic injury and promoted functional recovery through MIF-mediated AKT pathway. These findings suggest EPC-CM holds potential as a novel cell-free therapeutic approach for treating CCI through the actions of MIF.

Demographics, comorbidities, and comedications in newly diagnosed patients with Alzheimer's disease and related dementias: Findings from United States Medicare claims data.

Medicare claims data enables broad characterization of United States (US) patients with Alzheimer's disease and related dementias (ADRD). Resulting insights can be used as a reference to describe this population and as a benchmark for generalizability of patients with ADRD enrolled in clinical trials. To characterize demographics, comorbidities, comedications, and healthcare resource utilization in US patients with newly diagnosed ADRD, focusing on differences across Medicare fee-for-service (FFS) and Medicare Advantage enrollees. This observational cohort study used complete (100%) Medicare claims data inclusive of both FFS and Medicare Advantage insurance types. Study patients were ≥65-years-old with ≥12 months of continuous pre-index enrollment and Medicare Part D coverage. Two cohorts of patients were selected in calendar year 2019; those newly diagnosed with ADRD and those with a new acetylcholinesterase inhibitor (AChEI) claim. The newly diagnosed ADRD and new AChEI users cohorts included 861,727 and 395,319 patients, respectively. Demographics and comedications were generally similar across the two cohorts, supporting internal validity of the study results. Circulatory system-related comorbidities and mood disorders were common in both cohorts. Differences in race, inpatient claims and long-term care claims were observed between insurance types. The study results provide a reference for describing the ADRD population in the US and emphasize the importance of evaluating new Alzheimer's disease drugs in broad patient populations with comorbidities and concomitant medication use.

Changes in plasma biomarkers differentiate clinical stages of Alzheimer's disease using immunomagnetic reduction assays.

Many groups have been using immunomagnetic reduction (IMR) for assaying plasma amyloid-β 1-40 (Aβ1-40) peptide, Aβ1-42 peptide and total tau protein (T-Tau) in cognitively normal controls (NC), patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD). Tremendous results have been independently reported. We used traditional knowledge databases (e.g., PubMed, Embase), papers published at international conferences, and private communications to obtain data involving the use of IMR assay for plasma biomarkers of plasma Aβ1-40, Aβ1-42, and T-Tau in NC, aMCI, and ADD. Results of thirty studies were analyzed, including twenty-five studies published in papers, two studies presented at conferences and three unpublished studies. Among the thirty studies, there were 1189 subjects of NC, 544 aMCI patients and 853 ADD patients. The average value of plasma Aβ1-40 in subjects significantly decreased from NC (59.72 pg/ml) to aMCI (45.92 pg/ml, p < 0.0001), which was no significant different from ADD (48.34 pg/ml, p > 0.05). The average level of plasma Aβ1-42 significantly increased from NC (15.72 pg/ml) to aMCI (17.66 pg/ml, p < 0.0001), which was not significantly different from ADD (19.39 pg/ml, p > 0.05). However, the average level of plasma T-Tau significantly increased from NC (17.92 pg/ml) to aMCI (28.26 pg/ml, p < 0.0001), further significantly increased to AD (35.51 pg/ml, p < 0.001). Plasma Aβ1-40, Aβ1-42, and T-Tau levels are able to discriminate NC from patients with aMCI and ADD. Plasma T-Tau levels are disease-severity dependent.

The Anti-Elixir Triad: Non-Synced Circadian Rhythm, Gut Dysbiosis and Telomeric Damage.

Aging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells), reaches the limit of its ability to replicate, known as cellular or replicative senescence and consequently, the organs lose their physiological functions resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary life style and genetic abnormalities. These stress factors, can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.

Patterns of tau, amyloid and synuclein pathology in ageing, Alzheimer's disease and synucleinopathies.

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and β-amyloid. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised pathologically by α-synuclein aggregates. HP-tau and β-amyloid can also occur as copathologies in LB dementia, and a diagnosis mixedAD/DLB can be made if present in sufficient quantities. We hypothesised the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, β-amyloid, α-synuclein) and investigate the spatial distributions from tissue microarray (TMA) post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, β-amyloid and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, β-amyloid and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical (tauPC1) and temporolimbic (tauPC2) patterns were observed for HP-tau. For β-amyloid, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: 'posterior temporal - occipital (synPC1)', 'anterior temporal-frontal (synPC2)', 'parieto-cingulate-insula (synPC3)', and 'frontostriatal-amygdala (synPC4)'. Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1, tauPC2 and amylPC1 pattern scores (P≤0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n=65, P=0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1→ tauPC1 → global cognition) (P<0.05). Lastly, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P=0.02). In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype, and could, after necessary testing/validation, be integrated into semi-quantitative routine pathological assessment.

Sex-specific topological structure associated with dementia via latent space estimation.

We investigate sex-specific topological structures associated with typical Alzheimer's disease (AD) dementia using a novel state-of-the-art latent space estimation technique. This study applies a probabilistic approach for latent space estimation that extends current multiplex network modeling approaches and captures the higher-order dependence in functional connectomes by preserving transitivity and modularity structures. We find sex differences in network topology with females showing more default mode network (DMN)-centered hyperactivity and males showing more limbic system (LS)-centered hyperactivity, while both show DMN-centered hypoactivity. We find that centrality plays an important role in dementia-related dysfunction with stronger association between connectivity changes and regional centrality in females than in males. The study contributes to the current literature by providing a more comprehensive picture of dementia-related neurodegeneration linking centrality, network segregation, and DMN-centered changes in functional connectomes, and how these components of neurodegeneration differ between the sexes. We find evidence supporting the active role network topology plays in neurodegeneration with an imbalance between the excitatory and inhibitory mechanisms that can lead to whole-brain destabilization in dementia patients. We find sex-based differences in network topology with females showing more default mode network (DMN)-centered hyperactivity, males showing more limbic system (LS)-centered hyperactivity, while both show DMN-centered hypoactivity. We find that brain region centrality plays an important role in dementia-related dysfunction with a stronger association between connectivity changes and regional centrality in females than in males. Females, compared to males, tend to exhibit stronger dementia-related changes in regions that are the central actors of the brain networks. Taken together, this research uniquely contributes to the current literature by providing a more comprehensive picture of dementia-related neurodegeneration linking centrality, network segregation, and DMN-centered changes in functional connectomes, and how these components of neurodegeneration differ between the sexes.

Associations of Circulating Platelet Endothelial Cell Adhesion Molecule-1 Levels With Progression of Cerebral Small-Vessel Disease, Cognitive Decline, and Incident Dementia.

The association between platelet endothelial cell adhesion molecule-1 (PECAM-1) with cerebral small-vessel disease and cognition in dementia-free subjects remains uninvestigated. A prospective cohort of dementia-free subjects was recruited from memory clinics and followed up for 5 years. Annual neurocognitive assessments and twice-yearly brain magnetic resonance imaging scans were performed. Associations of baseline plasma PECAM-1 levels with cerebral small-vessel disease, cognitive decline (Montreal Cognitive Assessment scores and executive function Z scores), and incident dementia were evaluated. Of 213 subjects (aged 70.2±7.7 years, 51.2% men), median PECAM-1 levels were 0.790 (interquartile range, 0.645-0.955 ng/mL). Compared with the highest tertile, subjects within the lowest PECAM-1 tertile had greater cross-sectional white matter hyperintensity volume (β=4.84 [95% CI, 0.67-9.01]; P=0.023), age-related white matter change scores (β=1.39 [95% CI, 0.12-2.67]; P=0.033), and cerebral microbleeds (Adjusted risk ratio, 2.59 [95% CI, 1.19-5.62]; P=0.016). Of the 204 participants with follow-up data (median, 60.0 [interquartile range, 60.0-60.0] months), 24 (11.8%) developed incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM-1 had a higher risk of incident dementia (first tertile: adjusted hazard ratio [AHR], 4.52 [95% CI, 1.35-15.13]; P=0.024; second tertile: AHR, 3.28 [95% CI, 1.02-10.60]; P=0.047). The lowest PECAM-1 tertile was associated with greater progression of white matter hyperintensity volume (β=4.15 [95% CI, 0.06-8.24]; P=0.047), cerebral microbleeds (incident relative risk [IRR], 2.21 [95% CI, 1.05-4.65]; P=0.036), and decline in executive function (β=-0.45 [95% CI, -0.76 to -0.14]; P=0.004), and Montreal Cognitive Assessment (β=-1.32 [95% CI, -2.30 to -0.35]; P=0.008) scores. In dementia-free subjects, lower circulating PECAM-1 levels are associated with greater cerebral small-vessel disease progression and cognitive decline, thus warranting future study as a potential therapeutic target.

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation.

Mutations in GBA (glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson's disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred by GBA mutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in a Drosophila model of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressing Gba1b in activated macrophages suppressed head protein aggregation in Gba1b mutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also ameliorated Gba1b mutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.

The Intersecting Effects of Lifetime Experiences of Homelessness and Incarceration on Cognitive Aging and Dementia Risk Factors in the United States.

Alzheimer's disease and related dementias (ADRD) remain a pressing concern in the US, which also has one of the highest incarceration rates worldwide. Existing research has analyzed dementia risk and care among currently incarcerated and homeless populations; this paper fills a gap by examining later-life cognitive disparities facing formerly incarcerated and/or homeless individuals. Using Health and Retirement Study data (HRS; 1998-2018), we tested whether formerly homeless and/or incarcerated people had earlier onset of cognitive decline, and whether they were more likely to have modifiable risk factors for ADRD than those without such experiences. We estimated prevalence of mild cognitive impairment (MCI), dementia, and self-reported ADRD diagnosis. We also used repeated observations of cognitive functioning coupled with nested nonlinear regression to examine the onset of accelerated cognitive decline. Adjusting for demographic variables, formerly homeless and/or incarcerated participants have increased odds of having risk factors for dementia, including smoking, drinking alcohol, depression, mental illness, and discrimination from healthcare providers and police. Diagnosis of MCI and ADRD were more common among participants reporting a history of incarceration or homelessness. Nested nonlinear regression revealed that previous experiences of incarceration or homelessness-alone or together-are associated with earlier onset of accelerated cognitive decline compared to those who experienced neither. This study suggests that, even if they occur earlier in life, homelessness and incarceration experiences may increase risk of poorer cognitive health in late life. Future work is warranted to understand the lifelong consequences linked to this adversity.

Amyloid-beta metabolism in age-related neurocardiovascular diseases.

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood-brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed.

Neuropathological Heterogeneity of Dementia Due to Combined Pathology in Aged Patients: Clinicopathological Findings in the Vallecas Alzheimer’s Reina Sofía Cohort

Background/Objectives: Clinicopathological research in late-life dementia has focused recently on combined neurodegenerative and vascular conditions underlying the high phenotypic heterogeneity of patients. The Vallecas Alzheimer’s Reina Sofía (VARS) cohort (n &gt; 550), and particularly the series of associated brain donations (VARSpath cohort) are presented here. The aim of this study is to contribute to research in dementia with a well-characterized cohort from a single center. Methods: A total of 167 patients with complete neuropathological work-ups were analyzed here. The cohort is characterized by a high female predominance (79%), advanced age at death (88 yrs.), and a high frequency of ApoE-e4 haplotype (43%). Results: The main neuropathological diagnosis was Alzheimer’s disease (79.6%), followed by vascular dementia (10.2%) and Lewy body dementia (6%). Overall, intermediate-to-high cerebrovascular disease was observed in 38.9%, Lewy body pathology in 57.5%, LATE (TDP-43 pathology) in 70.7%, ARTAG in 53%, and argyrophilic grain disease in 12% of the patients. More than one pathology with a clinically relevant burden of disease was present in 71.1% of the brains, and a selection of premortem neuropsychological and functional scores showed significant correlation with the number of co-pathologies identified in postmortem brains. Conclusions: The VARS cohort, with thorough clinical follow-up, regular blood sampling, 3-Tesla MR, and a high rate of postmortem brain donation, can provide essential multidisciplinary data in the rising age of modifying therapies and biomarkers for Alzheimer’s disease and related dementias.